TWI856006B - Treatment of atopic dermatitis with moderate to severe excoriation - Google Patents

Abstract

Disclosed herein are methods for selectively treating atopic dermatitis (AD) in a subject having skin excoriations, pharmaceutical compositions for use in the treatment of atopic dermatitis in a subject having skin excoriations, uses of nemolizumab or an equivalent thereof in the manufacture of a medicament for the treatment of atopic dermatitis in a subject having skin excoriations, and methods of identifying a subject having atopic dermatitis that is likely to respond to nemolizumab treatment or an equivalent thereof.

Description

Treatment of atopic dermatitis with moderate to severe epidermal exfoliation

Described herein are methods for selectively treating atopic dermatitis (AD) in a subject with exfoliative skin disease, pharmaceutical compositions for treating atopic dermatitis in a subject with exfoliative skin disease, the use of nemolizumab or its equivalent in the manufacture of a medicament for treating atopic dermatitis in a subject with exfoliative skin disease, and methods for identifying subjects with atopic dermatitis who may respond to treatment with nemolizumab or its equivalent.

The following discussion is provided to assist the reader in understanding the present invention and is not considered to describe or constitute prior art thereof.

Atopic dermatitis ("AD," also known as atopic eczema) is a chronic inflammation of the skin that can cause itching (pruritus), swelling, redness and/or cracking of the skin. AD can be triggered by an immune response to an antigen, irritant, or mechanical stimulation. AD patients with pruritus may exhibit behaviors such as skin picking or skin massage. In some cases, AD patients with pruritus may avoid massage or picking. Persistent skin picking can lead to worsening of AD, disrupt sleep, and have a negative impact on the patient's psychosocial well-being. Some AD patients continue to suffer from pruritus even when other symptoms are effectively managed through treatment.

Approved treatments for pruritus include topical glucocorticoids and antihistamines, but they have limited effects in AD patients and/or are associated with significant side effects. Approved treatments for AD include calcineurin phosphatase inhibitors, emollients, and topical glucocorticoids. However, these treatments have limited efficacy in AD patients with moderate to severe AD. Although oral antihistamines are often prescribed for atopic dermatitis, these drugs have little to no effect on relieving pruritus. Nilizumab (CIM331) is a humanized monoclonal antibody that binds to interleukin-31 receptor A (IL-31RA) on cells (including neurons) to inhibit interleukin-31 signaling. Interleukin-31 is believed to play a role in the pathogenesis of AD and therefore may be an effective treatment for AD. However, there is still a need to develop novel treatment options for patients with AD, especially those who suffer from epidermal exfoliation or difficulty sleeping, and to identify patients who may respond to AD treatment.

Provided herein are methods for selectively treating atopic dermatitis (AD) in a subject with exfoliative skin, pharmaceutical compositions for treating atopic dermatitis in a subject with exfoliative skin, use of nilizumab or its equivalent in the manufacture of a medicament for treating atopic dermatitis in a subject with exfoliative skin, and methods for identifying subjects with atopic dermatitis who may respond to treatment with nilizumab or its equivalent.

According to some embodiments, a method of selectively treating atopic dermatitis in a subject suffering from skin exfoliation is provided, the method comprising administering to the subject an effective amount of nilizumab or an equivalent thereof, consisting of, or consisting essentially of the same.

In some embodiments of the methods, the epidermal exfoliation of the skin is moderate to severe. In some embodiments of the methods, the effective amount of nilizumab or its equivalent is in the range of about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. In specific embodiments, the effective amount of nilizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2.5 mg/kg. In some embodiments of the methods, nilizumab or its equivalent is administered topically or parenterally. In some embodiments of the methods, nilizumab or its equivalent is administered subcutaneously. In some embodiments, nilizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

According to some embodiments, a pharmaceutical composition for treating atopic dermatitis in a subject is provided, wherein the subject is determined to have one or more skin exfoliations, the composition comprising, consisting of, or consisting essentially of nilizumab or an equivalent thereof.

In some embodiments of the pharmaceutical composition, the epidermal exfoliation of the skin is moderate to severe. In some embodiments, the pharmaceutical composition further comprises a carrier. In some embodiments, the carrier is a pharmaceutically acceptable carrier.

According to some embodiments, there is provided a use of nilizumab or an equivalent thereof for the manufacture of a medicament for treating atopic dermatitis in an individual suffering from one or more skin exfoliations. In some embodiments, the skin exfoliations are moderate to severe.

According to some embodiments, a method of identifying an individual with atopic dermatitis who may be responsive to treatment with nilizumab or an equivalent thereof is provided, the method comprising detecting, consisting of, or consisting essentially of one or more epidermal exfoliations in the skin of the individual.

In some embodiments, the methods further comprise scoring the exfoliation as mild, moderate, or severe.

In some embodiments, the methods further comprise identifying the individual as likely to respond to treatment with nilizumab or its equivalent if moderate to severe one or more epidermal exfoliations are detected.

According to some embodiments, a method of treating a patient with atopic dermatitis is provided, the method comprising, consisting of, or consisting essentially of: (a) screening the patient with atopic dermatitis for one or more skin exfoliations; and (b) treating the patient screened in step (a) by administering an effective amount of nilizumab or an equivalent thereof.

In some embodiments of the methods, the epidermal exfoliation of the skin is moderate to severe. In some embodiments of the methods, the effective amount of nilizumab or its equivalent is in the range of about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. In specific embodiments, the effective amount of nilizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2.5 mg/kg. In some embodiments of the methods, nilizumab or its equivalent is administered topically or parenterally. In some embodiments of the methods, nilizumab or its equivalent is administered subcutaneously. In some embodiments, nilizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

According to some embodiments, a method of improving sleep quality in an individual suffering from atopic dermatitis and one or more skin exfoliations is provided, the method comprising administering to the individual an effective amount of nilizumab or an equivalent thereof. In some embodiments, the improvement in sleep quality is determined by detecting an improvement in one or more of: sleep onset latency, total sleep time, sleep efficiency, or wake time after sleep onset.

In some embodiments of the methods, the epidermal exfoliation of the skin is moderate to severe. In some embodiments of the methods, the effective amount of nilizumab or its equivalent is in the range of about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. In specific embodiments, the effective amount of nilizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, or about 2.5 mg/kg. In some embodiments of the methods, nilizumab or its equivalent is administered topically or parenterally. In some embodiments of the methods, nilizumab or its equivalent is administered subcutaneously. In some embodiments, nilizumab or its equivalent is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks.

Related applications

This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/628,714, filed on February 9, 2018, the entire contents of which are incorporated herein by reference.

Embodiments according to the present invention will be described more fully below. However, aspects of the present invention may be implemented in different forms and should not be considered limited to the embodiments described herein. Rather, these embodiments are provided so that the present invention will be sufficient and complete and will fully convey the scope of the present invention to those skilled in the art. The terms used in the description herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs. It should be further understood that terms (e.g., those terms defined in commonly used dictionaries) should be interpreted as having a meaning consistent with their meaning in the context of this application and the relevant art, and should not be interpreted in an idealized or overly formal sense unless expressly defined as such herein. Although not expressly defined below, such terms should be interpreted according to their commonly used meanings.

The terms used in the description herein are for the purpose of describing specific embodiments only and are not intended to limit the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference in their entirety.

Unless the context indicates otherwise, it is specifically intended that the various features of the present invention described herein may be used in any combination. In addition, the present invention also encompasses that in some embodiments, any feature or combination of features described herein may be excluded or omitted. For illustration, if the specification states that a complex comprises components A, B, and C, it is specifically intended that any one of A, B, or C or any combination thereof may be omitted and disclaimed, either individually or in any combination.

Unless expressly indicated otherwise, all specified embodiments, features, and terms are intended to include both the described embodiments, features, or terms and their biological equivalents.

As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless expressly stated otherwise.

It should be understood that, although not always explicitly stated, all numerical values are preceded by the term "about". The term "about" means that the number includes, but is not limited to, the exact number described herein, and is intended to refer to the number and substantially the same number without departing from the scope of the invention. As used herein, "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there is a use of the term that is not clear to those of ordinary skill in the art, then given the context in which the term is used, "about" will mean that the particular term is at most plus or minus 15%, 10%, 5%, 1% or 0.1%.

Also as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when explained in the alternative ("or").

As used herein, the terms "administer", "administration", and "administering" refer to (1) providing, giving, administering, and/or prescribing, as by or under the guidance of a health professional or his/her authorized agent, and (2) placing, taking, or consuming, as by a health professional or an individual. Administration should include but is not limited to oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), nasal, vaginal, rectal, sublingual, urethral (e.g., urethral suppository) or topical administration routes (e.g., gel, ointment, cream, aerosol, etc.), and can be formulated separately or together in suitable dosage unit formulations containing known non-toxic pharmaceutically acceptable carriers, adjuvants, excipients and vehicles suitable for each administration route. The present invention is not limited by the route of administration, formulation or administration schedule.

As used herein, the terms "treat", "treating" or "treatment" include alleviating, reducing or alleviating AD, pruritus or one or more symptoms thereof, regardless of whether AD and/or pruritus is considered "cured" or "healed" and regardless of whether all symptoms have subsided. Such terms also include reducing or preventing the progression of AD and/or pruritus or one or more symptoms thereof, hindering or preventing the underlying mechanisms of AD and/or pruritus or one or more symptoms thereof, and achieving any therapeutic and/or preventive benefits.

Interleukin 31 receptor subunit alpha ("IL-31RA", also known as NR10, glm-r and GPL) is a protein that forms a heterodimer with oncostatin M receptor (OSMR) and functions as an IL-31 receptor. There are multiple known splice variants of human-derived IL-31RA (WO 00/075314): NR10.1 consists of 662 amino acids and contains a transmembrane domain. NR10.2 is a soluble receptor-like protein consisting of 252 amino acids without a transmembrane domain. Meanwhile, known IL-31RA splice variants that function as transmembrane receptor proteins include NR10.3 and IL-31RAv3. Preferred IL-31RA variants include NR10.3 (also known as ILRAv4 (Nat Immunol 5, 752-60, 2004) and IL-31RAv3. NR 10.3 (IL31RAv4) consists of 662 amino acids (WO 00/075314; Nat Immunol 5, 752-60, 2004), and IL31RAv3 consists of 732 amino acids (GenBank Accession No.: NM-139017).

The amino acid sequence of IL31RAv4 is: The amino acid sequence of IL31RAv3 is: Mouse-derived IL-31RA includes a protein comprising the amino acid sequence: The cynomolgus macaque-derived IL-31RA includes a protein comprising the amino acid sequence:

As used herein, the term "subject" is used interchangeably with "patient" and refers to a mammal, particularly a human, horse, cow, pig, cat, dog, rodent, rat, or non-human primate. In preferred embodiments, the subject is a human. The subject may or may not need to be evaluated for skin scratching and/or skin exfoliation. In some embodiments, the subject is evaluated for skin scratching and/or skin exfoliation prior to administration of nilizumab treatment. In some embodiments, the subject is a child younger than 13 years old, younger than 8 years old, younger than 5 years old, younger than 3 years old, younger than 2 years old, or younger than 1 year old. In other embodiments, the subject is an adult.

The term "atopic dermatitis" (ie, "AD") is used herein as it is in this art and means chronic inflammation of the skin. The cause of AD is unknown but may involve genetics, immune system dysfunction, environmental exposures, and/or poor permeability of the skin. Symptoms of AD include, but are not limited to, pruritus, dry, itchy skin that may be worse at night, red to brownish-gray spots on the skin, especially on the hands, feet, ankles, wrists, neck, upper chest, eyelids, inside the bends of the elbows and knees, and in infants, face and scalp, small bumps that leak fluid and rashes when scratched, thickening of the skin, cracked skin, flaky skin, rough skin, sensitive skin, swollen skin, and disrupted sleep and/or insomnia. AD most often begins before age 5 and may continue into adolescence and adulthood. In some patients, AD redness and swelling occur periodically, followed by a period of clearance that can last for several years.

The term "pruritus" is used herein as it is in this art and refers to itching and/or itching sensations of the skin. Pruritus may be caused by AD or other diseases or conditions such as dry skin. In some cases, pruritus involves systemic itching of the skin all over the body. In some cases, pruritus is limited to specific areas of the body, such as on the arms or legs. Pruritus may be chronic or acute. Symptoms of pruritus include, but are not limited to, flaking of the skin epidermis, redness, bumps, spots, blisters, dry skin, cracked skin, and a leathery or flaky texture of the skin. In some cases, pruritus does not cause detectable skin changes. Behavioral responses to pruritus include, but are not limited to, skin picking and/or skin massaging. In some cases, skin picking can result in exfoliation ranging from mild to severe. In some cases, patients with pruritus avoid picking and/or massaging the skin. Traditional treatments for pruritus include, but are not limited to, skin moisturizers, topical emollients, antihistamines (such as diphenhydramine), corticosteroids (such as hydrocortisone topical cream), counterirritants (such as peppermint oil, menthol or camphor, crotamiton), antipruritics (commonly used to treat scabies), local anesthetics (such as benzocaine topical cream), and phototherapy. The most common type of light used in phototherapy is UVB.

As used herein, the term "antibody" collectively refers to immunoglobulins or immunoglobulin-like molecules, which include, but are not limited to, IgA, IgD, IgE, IgG and IgM, combinations thereof, or fragments thereof, by way of example. Fragments of antibodies include, but are not limited to, Fab fragments and single-chain variable fragments (scFv) and similar molecules produced during an immune response in any vertebrate, such as mammals (such as humans, goats, rabbits and mice) and non-mammalian species (such as shark immunoglobulins).

In terms of antibody structure, immunoglobulins generally have a heavy (H) chain and a light (L) chain interconnected by disulfide bonds. There are two types of light chains: lambda (λ) and kappa (κ). There are five major classes (or isotypes) of heavy chains that determine the functional activity of the antibody molecule: IgM, IgD, IgG, IgA, and IgE. Each heavy and light chain contains a constant region and a variable region, (these regions are also called "domains"). In combination, the heavy and light chain variable regions, also called the "Fab region," specifically bind antigen. The light and heavy chain variable regions contain a "framework" region interspersed with three hypervariable regions, also called "complementary determining regions" or "CDRs." The extent of the framework regions and CDRs has been defined (see Kabat et al., Sequences of Proteins of Immunological Interest, U.S. Department of Health and Human Services, 1991, which is incorporated herein by reference). The Kabat database is maintained online. The sequences of the framework regions of the different light or heavy chains are relatively conserved within species. The framework regions of an antibody, i.e., the combined framework regions that make up the light and heavy chains, mostly adopt a b-sheet conformation, and the CDRs form loops connecting the b-sheet structure and in some cases form part of the b-sheet structure. Thus, the framework regions serve to form a skeleton that provides for the positioning of the CDRs in the correct orientation by non-covalent interactions between the chains.

The CDRs are primarily responsible for binding to the antigenic determinant of an antigen. The CDRs of each chain are generally referred to as (numbered sequentially from the N-terminus) CDR1, CDR2, and CDR3, and are also identified by the chain in which a particular CDR is located. Thus, the _VH CDR3 in the antibody in which it is found is located in the heavy chain variable domain of that antibody, while the _VL CDR1 is the CDR1 from the light chain variable domain of that antibody in which it is found. An antibody that binds to IL-31RA will have specific _VH and _VL region sequences, and therefore specific CDR sequences. Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. Although the CDRs vary from antibody to antibody, only a limited number of amino acid positions within the CDRs are directly involved in antigen binding. These positions within the CDR are called specificity determining residues (SDR). The bases of the antibody play a role in regulating the activity of immune cells. This region is called the Fc fragment region (Fc) and is composed of two heavy chains contributing to two or three constant domains, depending on the class of the antibody. The Fc region serves to ensure that each antibody generates an appropriate immune response to a given antigen by binding to a specific class of proteins found on certain cells (such as B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, etc.) and is called an "Fc receptor." Because the constant domains of the heavy chain make up the Fc region of the antibody, the class of the heavy chain in the antibody determines its class effect. The heavy chains in antibodies include a, g, d, e, and m, and are respectively associated with the antibody isotypes IgA, G, D, E, and M. This suggests that different isotypes of antibodies have different class effects due to their different Fc regions binding and activating different types of receptors.

There are four subclasses of IgG, which are the most abundant antibody isotypes found in human serum. The four subclasses, IgG1, IgG2, IgG3 and IgG4, are highly conserved. See generally the World Wide Web: ncbi.nlm.nih.gov/pmc/articles/PMC4202688/. The amino acid sequences of the constant regions of these peptides are known in the art, see, for example, Rutishauser, U. et al. (1968) "Amino acid sequence of the Fc region of a human gamma G-immunoglobulin" PNAS 61(4):1414-1421; Shinoda et al. (1981) "Complete amino acid sequence of the Fc region of a human delta chain" PNAS 78(2):785-789; and Robinson et al. (1980) "Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511)" PNAS 77(8):4909-4913. Therapeutic Antibodies

"Nilizumab" is a humanized monoclonal antibody that binds to IL-31RA. Nilizumab is labeled as follows: immunoglobulin G2-κ, anti-[homo sapiens IL31RA (interleukin 31 receptor subunit)], humanized monoclonal antibody; γ2 heavy chain (1-445) [humanized VH (homo sapiens IGHV1-2*02 (83.70%) -(IGHD)-IGHJ5*01) [8.8.14] (1-121) -homo sapiens IGHG2*01 (CH1 C10＞S (135), R12＞K (137), E16＞G (141), S17＞G (142) (122-219), hinge C4＞S (223) (220-231), CH2 H30＞Q (268) (232-340), CH3 R11＞Q (355), Q98＞E (419) (341-445)) (122-445)], with (224- 214')-disulfide bond of kappa light chain (1'-214') [humanized V-κ (Homo sapiens IGKV1-39*01 (82.10%) - IGKJ4*01) [6.3.9] (1'-107') - Homo sapiens IGKC*01 (108'- 214')]; dimer (227-227":230-230")-double disulfide bond. Nilizumab has disulfide bridges at the following positions: Endo-H (C23-C104) 22-96 148-204 261-321 367-425 22''-96'' 148''-204'' 261''-321'' 367''-425''; Endo-L (C23-C104) 23'-88' 134'-194' 23'''-88''' 134'''-194'''; Meta-H-L (h 5-CL 126) 224-214' 224''-214'''; Meta-H-H (h 8, h 11) 227-227'' 230-230''. Nilizumab has N-glycosylation sites at the following positions: H CH2 N84.4: 297, 297''. Nilizumab lacks the C-terminal glycine and lysine of the H chain (CHS G1＞del, K2＞del).

Nilizumab heavy chain amino acid sequence:

Nilizumab light chain amino acid sequence:

The variable domains of the heavy and light chain sequences are shown above in bold, and the CDR sequences are underlined.

Antibodies equivalent to nilizumab include, but are not limited to: (i) antibodies having heavy chains comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the heavy chain sequence of nilizumab, (ii) antibodies having light chains comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the light chain sequence of nilizumab, (iii) antibodies having variable regions comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the variable region sequence of nilizumab. %, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to a CDR sequence of nilizumab, (iv) an antibody having CDRs comprising at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to a CDR sequence of nilizumab, (v) an antibody that binds to the same isoform of IL-31RA as nilizumab (e.g., IL31-RAv3), optionally the same antigenic determinant of IL-31RA, (vi) an antibody that blocks or neutralizes IL-31RA, (vii) an antibody that binds to oncostatin M receptor (OSMR), and (viii) combinations thereof. For example, suitable equivalents include those having the same or substantially similar heavy and light chain amino acid sequences as nilizumab. Immunoglobulins or immunoglobulin-like molecules Additional exemplary nilizumab equivalents are described, for example, in WO 2010/064697.

The equivalent of Nilizumab may be a monoclonal or polyclonal antibody. Such monoclonal antibodies having IL31-RA binding and/or neutralizing activity can be obtained, for example, by the following procedure: by preparing anti-IL31-RA monoclonal antibodies using an antigen IL31-RA or a fragment thereof derived from a mammal (such as a human or mouse) by a known method, and then antibodies having IL31-RA binding and/or neutralizing activity are selected from the anti-IL31-RA monoclonal antibodies thus obtained. Specifically, according to known immunization methods, the desired antigen or cells expressing the desired antigen are used as sensitizing antigens for immunization. Anti-IL31-RA monoclonal antibodies can be prepared by fusing the obtained immune cells with known parental cells using a known cell fusion method and screening the monoclonal antibody-producing cells (hybridoma) by a known screening method. Animals to be immunized include, for example, mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cows, horses and pigs. Antigens can be prepared according to known methods, for example, by methods using bacilli (e.g., WO 98/46777) using known IL31-RA gene sequences.

Fusion tumors can be prepared, for example, according to the method of Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981) 73: 3-46). When the immunogenicity of the antigen is low, immunization can be performed after the antigen is linked to an immunogenic macromolecule (such as albumin). The antigen used to prepare a monoclonal antibody having binding and/or neutralizing activity against human IL31-RA is not particularly limited, as long as it can prepare an antibody having binding and/or neutralizing activity against human IL31-RA. For example, it is known that there are a variety of variants of human IL31-RA, and any variant can be used as an immunogen as long as it can prepare an antibody having binding and/or neutralizing activity against human IL31-RA. Alternatively, under the same conditions, a peptide fragment of IL31-RA or a protein in which artificial mutations have been introduced into the natural IL31-RA sequence can be used as an immunogen. Human IL31-RA.3 is one of the preferred immunogens for preparing antibodies having the activity of binding to and/or neutralizing IL31-RA in the present invention.

The IL31-RA binding activity of equivalent antibodies can be determined by methods known to those skilled in the art. Methods for determining the antigen binding activity of antibodies include, for example, ELISA (enzyme-linked immunosorbent assay), EIA (enzyme immunoassay), RIA (radioimmunoassay), and fluorescent antibody methods. For example, when using enzyme immunoassay, an antibody sample, such as purified antibody and culture supernatant of antibody-producing cells, is added to an antigen-coated plate. A secondary antibody labeled with an enzyme (such as alkaline phosphatase) is added and the plate is incubated. After washing, an enzyme substrate, such as p-nitrophenyl phosphate, is added, and the absorbance is measured to evaluate the antigen binding activity. The binding and/or neutralizing activity of equivalent antibodies against IL31-RA can be measured, for example, by observing the effect of inhibiting the growth of IL-31-dependent cell lines. For example, the activity of purified mouse IL-31 antibodies can be analyzed by evaluating the IL-31-dependent growth of Ba/F3 cells transfected with mouse IL-31 receptor α and mouse OSMR genes. Epidermal shedding as a biomarker for response to nilizumab treatment

The inventors hypothesized that anti-itch medications may have a greater effect on AD in patients who suffer from skin scratching due to pruritus than in patients who do not scratch. Without being bound by theory, it is believed that the itch-scratch cycle is not only a symptom of AD, but also an exacerbating factor of AD in the subset of AD patients who scratch their skin in response to pruritus. In the itch-scratch cycle, the strong effects of scratching promote susceptibility to increased itching and worsening of skin lesions, known as excoriation.

A targeted approach to identifying individuals who suffer from skin picking due to pruritus is to identify individuals with epidermal excoriation caused by picking. Epidermal excoriation refers to skin damage caused by trauma, such as picking or abrasions. In some embodiments of the methods described herein, epidermal excoriation can be identified by the presence, number, and/or intensity of lesions having one or more of the following characteristics: linearity, fissures or breaks in the skin surface, scabies, serous crust, blood, redness, skin abrasions, or skin tears. Split epidermal excoriation is epidermal excoriation with linear fissures through the epidermis into the underlying dermis.

In some embodiments, epidermal exfoliation is scored as none, mild, moderate, or severe. "None," "mild," "moderate," and "severe" are terms of the art that describe the presence, extent, and/or intensity of epidermal exfoliation. Those skilled in the art know the boundaries and limits of these terms. For example, methods for assessing atopic dermatitis used by health care professionals and comprising scoring epidermal exfoliation as none, mild, moderate, and severe include, but are not limited to: Atopic Dermatitis Assessment Measure (ADAM), Eczema Area and Severity Index (EASI), Self-Administered EASI (SA-EASI), Scoring Atopic Dermatitis (SCORAD), Six Areas Six Signs Atopic Dermatitis Index (SASSAD), Simple Scoring System (SSS), and Three Severity Scores (TIS). In some embodiments, the score is represented by a null number 0, a mild score is represented by a number 1, a moderate score is represented by a number 2, and a severe score is represented by a number 3.

As used herein, the term "none to mild" refers to skin epidermal exfoliation scored as none, mild, or therebetween. In some embodiments, "none to mild" refers to skin epidermal exfoliation scored as 0, 1, 1.5, 0 to 1, ≤ 1, or < 2. In some embodiments, "none to mild" refers to a range of skin epidermal exfoliation scores of about 0 to about 1. As used herein, the term "moderate to severe" refers to skin epidermal exfoliation scored as moderate, severe, or therebetween. In some embodiments, "moderate to severe" refers to skin epidermal exfoliation scored as 2, 2.5, 3, 2 to 3, or ≥ 2. In some embodiments, "moderate to severe" refers to a range of skin epidermal exfoliation scores of about 2 to about 3.

In some embodiments, epidermal exfoliation is scored according to one or more of the following methods: SCORAD (disclosed in Stalder, JF et al., Dermatol (1993), 186: 23-31, the entire disclosure of which is incorporated herein by reference), patient-directed SCORAD (disclosed in Vourc'h-Jourdain, M. et al., Dermatology (2009) 218: 246-51, the entire disclosure of which is incorporated herein by reference), ADAM (disclosed in Charman, D. et al., J. Outcome Meas. (1999) 3: 21-34, the entire disclosure of which is incorporated herein by reference), EASI (disclosed in Tofte, SJ et al., J Eur Acad Dermatol Venereol (1998) 11: S197, the entire disclosure of which is incorporated herein by reference), SA-EASI (disclosed in TS et al ., Br J Dermatol (2002) 147: 1192-8, the entire disclosure of which is incorporated herein by reference), SASSAD (disclosed in Berth-Jones, J., Br J Dermatol (1996) 135: 25-30, the entire disclosure of which is incorporated herein by reference), SSS (disclosed in Costa, C. et al., Acta Derm Venereol (1989) 69: 42-5, the entire disclosure of which is incorporated herein by reference), and TIS (disclosed in Wolkerstorfer, A. et al., Acta Derm. Venereol. (1999) 79: 356-59, the entire disclosure of which is incorporated herein by reference). In a preferred embodiment, epidermal exfoliation is scored according to the SCORAD and/or PO-SCORAD method.

The SCORAD method (SCORAD and PO-SCORAD) is a method for determining the severity of AD that includes scoring epidermal shedding as absent (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3) based on the presence and intensity of epidermal shedding at representative epidermal shedding sites. Representative epidermal shedding sites are sites that contain epidermal shedding of average intensity across individuals. Scoring of epidermal shedding according to the SCORAD method does not include scoring based on a score (e.g., a half-point score, such as 0.5, 1.5, or 2.5). Exemplary images of scoring epidermal exfoliation according to the SCORAD epidermal exfoliation method are provided in Figures 1A-1C, Figures 2A-2D, Stalder et al. (1993) and Oranje, A.P. et al. (Pediatr. Allergy Immunol. (1997) 8: 28-34, the entire disclosures of which are incorporated herein by reference).

The EASI method (EASI and SA-EASI) is a method of determining the severity of eczema that involves scoring exfoliation as none (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3) based on the average exfoliation intensity in each of four body areas: head and neck, trunk, upper limbs, and lower limbs. Areas of the body with no epidermal shedding are scored as none (score = 0), epidermal shedding that is only perceptible, inadequate, and/or superficial is scored as mild (score = 1), epidermal shedding that includes much superficial and/or some deep epidermal shedding is scored as moderate (score = 2), and scattered large areas of superficial epidermal shedding and/or much deep epidermal shedding is scored as severe (score = 3). In the EASI method, half scores (e.g., 2.5) are allowed. However, a score of 0.5 is not allowed because the minimum score for the presence of epidermal shedding under the EASI method is mild (score = 1). An atlas of representative images of epidermal shedding scored by the EASI method is provided in Figures 3A-3D.

The ADAM method is a method for determining the severity of AD that involves scoring epidermal exfoliation based on the total number of epidermal exfoliations present on an individual's skin. Fewer than 5 epidermal exfoliations are scored as 0, 5 to 20 epidermal exfoliations are scored as 1, more than 20 epidermal exfoliations are scored as 2, and cracked epidermal exfoliations are scored as 3.

The SASSAD method is a method of determining the severity of AD that involves scoring epidermal exfoliation as absent (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3) based on the prominence of epidermal exfoliation at the worst affected site of exfoliation in each of six areas of the individual: hands, arms, feet, legs, head/neck, and trunk. The SASSAD method defines exfoliation as any injury to the skin caused by picking but not by erythema or itching. Under the SASSAD method, epidermal exfoliation is absent even if it cannot be detected with certainty after careful examination, mild epidermal exfoliation is epidermal exfoliation present that requires careful examination to observe, moderate epidermal exfoliation is epidermal exfoliation present that is immediately apparent, and severe epidermal exfoliation is epidermal exfoliation present that is very prominent.

The SSS method is a method for determining the severity of AD, which includes scoring the severity of epidermal peeling and cracking as none (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3) based on the severity of each of 20 sites on the individual: scalp, ears, cheeks, eyes, face, neck, chest, abdomen, back, elbows, arms, axillae, hands and dorsal wrists, palms and wrists, buttocks and groin, popliteal space, thighs, legs, arches, and soles.

Similar to SCORAD, the TIS method is a method for determining the severity of AD that includes scoring epidermal shedding on a scale of none (score = 0), mild (score = 1), moderate (score = 2), or severe (score = 3) based on the presence and intensity of epidermal shedding at the most representative epidermal shedding site. A representative epidermal shedding site is a site that contains epidermal shedding of average intensity for an individual. Scoring of epidermal shedding according to the TIS method does not include scoring based on points (e.g., half-point scores, such as 0.5, 1.5, or 2.5).

To test the hypothesis that AD patients who suffer from skin picking due to pruritus are a subpopulation of patients who respond to nilizumab treatment, published data from a study of adults with moderate to severe AD treated with subcutaneous nilizumab (Ruzicka, T. et al. N. Engl. J. Med. (2017), 376: 826-35, the entire disclosure of which is incorporated herein by reference) were analyzed to determine the treatment effect in patients with signs of picking. Based on skin exfoliation, AD patients from the Ruzicka et al. nilizumab study were divided into two groups: (i) AD patients with no to mild exfoliation at baseline; and (ii) AD patients with moderate to severe exfoliation at baseline. Epidermal exfoliation was scored according to the SCORAD method. Study parameters were then analyzed to compare the relative treatment effects of each group compared to placebo.

The Ruzicka et al. study of nivolumab was a phase 2, randomized, double-blind, placebo-controlled trial lasting 12 weeks and included 264 patients (clinical trial number NCT01986933). Eligible patients were adults with moderate to severe atopic dermatitis that was not adequately controlled by topical therapy. Patients were not eligible for the study if they had active dermatologic disease associated with AD. Enrolled patients received subcutaneous nivolumab or placebo at a dose of 0.1 mg/kg, 0.5 mg/kg, or 2.0 mg/kg every 4 weeks. Some patients alternatively received a dose of 2.0 mg/kg every 8 weeks. The primary endpoint of the study was improvement in the pruritus visual analog scale (VAS) score. Additional endpoints included improvements in body surface area of atopic dermatitis and the Eczema Area and Severity Index (EASI). At the end of the study, the greatest percentage change in EASI score at 12 weeks, -42.3%, occurred in the group receiving 0.5 mg/kg nilizumab every 4 weeks. This dose also presented the best benefit-risk profile. However, improvements in EASI scores were also observed in the other dose groups (-23.0% in the 0.1 mg group and -40.9% in the 2.0 mg group). Improvements were also observed in VAS scores across doses.

The results of the inventor's analysis of the Ruzicka et al. study of nilizumab are presented in Tables 1 and 2 below. Pruritus VAS scores range from 0 (no itching) to 100 (worst itching imaginable) and are recorded daily by patients using an electronic reporting tool. Negative changes in VAS scores indicate improvement. EASI scores range from 0 to 72, with higher scores indicating worse disease severity. Investigator Global Assessment (IGA) scores range from 0 (clear) to 5 (extremely severe disease) and are presented as a percentage of patients in the indicated group. Sleep refers to sleep measurements recorded by actigraphy, which records whole body movements and is a validated motion detection method for recording sleep measurements (including sleep efficiency). Sleep efficiency was total sleep time divided by total time in bed. Dermatology Life Quality Index (DLQI) scores ranged from 0 to 30, with higher scores indicating lower quality of life. To be eligible for the Ruzicka et al study, patients were required to have a baseline EASI score of at least 10, a baseline pruritus VAS score of at least 50 mm, and a baseline IGA score of at least 3.

As shown in Table 1, the two groups of AD patients in the study presented comparable levels of pruritus, DLQI, and sleep efficiency. Although EASI and IGA were not balanced between the two groups, this was expected since these two parameters are affected by the presence or absence of epidermal exfoliation. Table 1 : Baseline Clinical Characteristics

As shown in Table 2, the presence of epidermal exfoliation affects the efficacy of nilizumab treatment in AD patients. Treatment outcomes at 12 weeks were improved for all parameters in the patient group with moderate to severe epidermal exfoliation. These results were generated by comparing the net effect (nilizumab effect - placebo effect) between the two groups. For example, after treatment with nilizumab, patients with no to mild epidermal exfoliation showed a 13% improvement in sleep efficiency. In contrast, patients with moderate to severe epidermal exfoliation showed a 39% improvement in sleep efficiency, a response that was three times better than the no to mild epidermal exfoliation group. Table 2 : Treatment outcomes

The data presented in Table 2 demonstrate that the presence of moderate to severe epidermal exfoliation is a biomarker for predicting the efficacy of nilizumab treatment in AD patients.

Thus, provided herein are methods for identifying an individual with atopic dermatitis who may respond to treatment with nilizumab or an equivalent thereof, the method comprising detecting, consisting of, or consisting essentially of one or more epidermal exfoliations in the skin of the individual. In some embodiments, provided herein are methods for determining whether an individual with atopic dermatitis is likely to respond to treatment with nilizumab or an equivalent thereof, the method comprising detecting, consisting of, or consisting essentially of one or more epidermal exfoliations in the skin of the individual. In some embodiments, provided herein is a method of predicting whether an individual with atopic dermatitis is likely to respond to treatment with nilizumab or an equivalent thereof, the method comprising detecting, consisting of, or consisting essentially of one or more exfoliations of the skin of the individual. In some embodiments, the exfoliation of the skin is caused by pruritus.

In some embodiments, the methods include detecting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more skin exfoliations. In some embodiments, the extent of skin exfoliation is detected by detecting the total skin surface area affected, the number and/or size of affected areas, or the percentage of affected surface area. In some embodiments, exfoliation is detected at a specific area or site of the skin of an individual, including exfoliation that represents the average intensity of exfoliation in individuals. In some embodiments, epidermal exfoliation is detected at specific areas or locations of the skin of an individual, including epidermal exfoliation that represents the worst (i.e., most severe) intensity of epidermal exfoliation. In some embodiments, the average intensity or worst intensity of epidermal exfoliation is detected at one or more of the following locations of an individual: hands, arms, feet, legs, head, neck, head and neck, trunk, upper limbs, lower limbs, scalp, ears, cheeks, eyes, face, neck, chest, back, elbows, arms, armpits, hands and dorsal wrists, palms and wrists, buttocks and groin, popliteal fossa, thighs, legs, arches of the feet, and soles of the feet. In some embodiments, epidermal exfoliation is detected by a health care professional. In some embodiments, epidermal exfoliation is detected by the individual or an adult guardian of the individual.

In some embodiments, the methods further comprise scoring epidermal exfoliation as mild, moderate or severe according to the criteria described herein. In some embodiments, epidermal exfoliation is scored as none (score of 0), mild (score of 1), moderate (score of 2) or severe (score of 3) according to SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS and/or TIS methods. In preferred embodiments, epidermal exfoliation is scored according to SCORAD or PO-SCORAD methods. In some embodiments, epidermal exfoliation is scored by a health care professional. In some embodiments, epidermal exfoliation is scored by the individual or an adult guardian of the individual.

In some embodiments, the methods further comprise identifying the individual as likely to respond to treatment with nilizumab or its equivalent if epidermal exfoliation scored as moderate to severe is detected. In some embodiments, the methods further comprise determining that the individual with atopic dermatitis is likely to respond to treatment with nilizumab or its equivalent if epidermal exfoliation scored as moderate to severe is detected. In some embodiments, the methods further comprise predicting that the individual with atopic dermatitis is likely to respond to treatment with nilizumab or its equivalent if epidermal exfoliation scored as moderate to severe is detected.

In some embodiments, the methods further comprise identifying the individual as unlikely to respond to treatment with nilizumab or its equivalent if no epidermal exfoliation scored as none to mild is detected. In some embodiments, the methods further comprise determining that the individual with atopic dermatitis is unlikely to respond to treatment with nilizumab or its equivalent if no epidermal exfoliation scored as none to mild is detected. In some embodiments, the methods further comprise predicting that the individual with atopic dermatitis is unlikely to respond to treatment with nilizumab or its equivalent if no epidermal exfoliation scored as none to mild is detected. Pharmaceutical Compositions

Provided herein is a pharmaceutical composition for treating atopic dermatitis in an individual diagnosed with one or more skin exfoliations, the composition comprising, consisting of, or consisting essentially of nilizumab or its equivalent. In addition, the present invention provides a therapeutic agent for AD comprising nilizumab or its equivalent as an active ingredient.

In some embodiments, epidermal exfoliation is pre-detected and/or scored by a health care professional, by an individual, or by an adult guardian of the individual. In some embodiments, epidermal exfoliation is scored according to one or more of the SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and/or TIS methods. In a preferred embodiment, epidermal exfoliation is scored according to the SCORAD or PO-SCORAD methods. In some embodiments, epidermal exfoliation is scored as moderate to severe. In some embodiments, epidermal exfoliation is scored from 2 to 3. In some embodiments, the individual does not suffer from skin epidermal exfoliation scored as none to mild. In some embodiments, epidermal exfoliation is not scored from 0 to 1. In some embodiments, the skin exfoliation is not mild. In some embodiments, the scored exfoliation is at a specific area or site of the skin of an individual, the skin comprising an exfoliation representing an average intensity for an individual with exfoliation. In some embodiments, the scored exfoliation is at a specific area or site of the skin of an individual, the skin comprising an exfoliation representing the worst intensity for an individual with exfoliation. In some embodiments, the skin exfoliation is caused by pruritus. In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin exfoliations.

The phrase "comprising nilizumab or its equivalent as an active ingredient" means comprising nilizumab or its equivalent as at least one of the active ingredients, and the ratio of the antibody is not limited. In addition, the therapeutic agent for AD used in the present invention may also include other ingredients that enhance the treatment of AD in combination with nilizumab or its equivalent. For example, the composition may include one or more calcineurin phosphatase inhibitors (e.g., topical calcineurin phosphatase inhibitors), a skin moisturizer, a topical steroid (such as a topical glucocorticoid), and an oral antihistamine.

The pharmaceutical composition of nilizumab or its equivalent of the present invention can be prepared as a formulation according to standard methods (see, for example, Remington's Pharmaceutical Science, Mark Publishing Company, Easton, USA). In some embodiments, the pharmaceutical composition comprises a carrier and/or an additive. In some embodiments, the carrier is a pharmaceutically acceptable carrier. For example, in some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., PEG and Tween), excipients, antioxidants (e.g., ascorbic acid), coloring agents, flavoring agents, preservatives, stabilizers, buffers (e.g., phosphoric acid, citric acid and other organic acids), chelating agents (e.g., EDTA), suspending agents, isotonic agents, binders, disintegrants, lubricants, flow-promoting agents, Agents, corrective agents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl acetal diethylamino acetate, polyvinyl pyrrolidone, gelatin, medium and long chain fatty acid triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethyl cellulose, corn starch and inorganic salts. In some embodiments, the pharmaceutical composition comprises one or more other low molecular weight polypeptides, proteins (such as serum albumin, gelatin and immunoglobulins) and amino acids (such as glycine, glutamine, asparagine, arginine and lysine).

When nilizumab or its equivalent is prepared as an aqueous solution for injection, nilizumab or its equivalent can be dissolved in an isotonic solution containing, for example, physiological saline, dextrose or other adjuvants. Adjuvants may include, for example, D-sorbitol, D-mannose, dextrose mannitol and sodium chloride. In addition, appropriate solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol and PEG) and non-ionic detergents (polysorbate 80 and HCO-50) may be used simultaneously.

If necessary, nilizumab or its equivalent can be encapsulated in microcapsules (microcapsules made of hydroxymethylcellulose, gelatin, polymethyl methacrylate and the like) and made into components of colloidal drug delivery systems (liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) (for example, see "Remington's Pharmaceutical Science 16th Edition" &, Oslo Ed. (1980)). Additional methods for preparing sustained-release drugs are known, and these can be applied to nilizumab or its equivalents (Langer et al., J. Biomed. Mater. Res. (1981) 15, 167-277; Langer, Chem. Tech. (1982) 12, 98-105; U.S. Patent No. 3,773,919; European Patent Application (EP) No. 58,481; Sidman et al., Biopolymers (1983) 22, 547-56; EP 133,988).

The pharmaceutical composition of the present invention can be administered orally or parenterally, but parenterally is preferred. Specifically, the pharmaceutical composition is administered to the patient by injection or percutaneous administration. Injection includes, for example, intravenous injection, intramuscular injection, and subcutaneous injection for systemic or local administration. The pharmaceutical composition can be administered to the site of inflammation to be suppressed or to the area around the site by local infusion or intramuscular injection. In some embodiments, the pharmaceutical composition is administered at or near one or more skin epidermal exfoliation sites.

The administration method can be appropriately selected according to the age and condition of the patient. The single administration dose can be selected, for example, from the range of 0.0001 to 100 mg/kg body weight of the active ingredient. Alternatively, for example, when the agent is administered to a human patient, the dose of the active ingredient can be selected from the range of 0.001 to 1,000 mg/kg body weight. In some embodiments, the compositions are formulated to administer an amount containing, for example, about 0.01 to 50 mg/kg, about 0.01 mg/kg to about 0.1 mg/kg, about 0.05 mg/kg to 0.15 mg/kg, about 0.1 mg/kg to about 0.6 mg/kg, about 0.1 mg/kg to about 1 mg/kg, about 0.25 mg/kg to about 0.75 mg/kg, about 0.4 mg/kg to about 0.8 mg/kg, about 0.4 mg/kg to about 1.8 mg/kg, about 0.5 to about 2.5 mg/kg, about 0.8 mg/kg to about 2.2 mg/kg, about 1 mg/kg to about 2.5 mg/kg, about 1 mg/kg to about 3.5 mg/kg, about 1 mg/kg to about 5 mg/kg, about 2 mg/kg to about 4 mg/kg, about 2.5 mg/kg to about 10 mg/kg, about 5 In some embodiments, the dosage of nilizumab or its equivalent is about 100 mg/kg to about 10 mg/kg, about 10 mg/kg to about 20 mg/kg, about 10 mg/kg to about 40 mg/kg, about 20 mg/kg to about 50 mg/kg, about 25 mg/kg to about 75 mg/kg, about 50 mg/kg to about 100 mg/kg, or about 100 mg/kg to about 500 mg/kg, or about 100 mg/kg to about 1000 mg/kg of body weight. In preferred embodiments, the dosage is about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 10 mg/kg. In some embodiments, the dosage is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 500 mg/kg or about 1,000 mg/kg. In certain embodiments, the effective amount of nilizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg or about 2.5 mg/kg. In a preferred embodiment, the amount is about 0.5 mg/kg.

In some embodiments, a single dose can be selected, for example, from 1 to 100 mg of the active ingredient (i.e., nilizumab or its equivalent), or more specifically from about 10 to about 90 mg, about 20 to about 80 mg, about 25 to about 70 mg, or about 30 to about 60 mg. For example, in some embodiments, a single dose can be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 about, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

In some embodiments, a single dose may vary over time. For example, a subject may receive an initial "starting dose" that is higher than a "maintenance dose" that is subsequently administered. In some embodiments, a subject may be administered one or more initial starting doses of 60 mg of nivolumab (or its equivalent) followed by subsequent maintenance doses of 30 mg. In other embodiments, the initial dose and subsequent doses may be the same. For example, the initial dose and subsequent dose may be 60 mg. In any of these embodiments, the antibody (nivolumab or its equivalent) may be administered to the subject with or without a second active agent (such as a topical steroid or a topical calcineurin phosphatase inhibitor). Treatment

According to some embodiments, a method of selectively treating atopic dermatitis in a subject suffering from one or more skin exfoliations is provided, the method comprising administering to the subject an effective amount of nilizumab or an equivalent thereof, consisting of, or consisting essentially of the same.

In some embodiments, epidermal exfoliation is pre-detected and/or scored by a health care professional, by an individual, or by an adult guardian of the individual. In some embodiments, epidermal exfoliation is scored according to one or more of the SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and/or TIS methods. In a preferred embodiment, epidermal exfoliation is scored according to the SCORAD or PO-SCORAD methods. In some embodiments, epidermal exfoliation is scored as moderate to severe. In some embodiments, epidermal exfoliation is scored from 2 to 3. In some embodiments, the individual does not suffer from skin epidermal exfoliation scored as none to mild. In some embodiments, epidermal exfoliation is not scored from 0 to 1. In some embodiments, the skin exfoliation is not mild. In some embodiments, the scored exfoliation is at a specific area or site of the skin of an individual, the skin comprising an exfoliation representing an average intensity for an individual with exfoliation. In some embodiments, the scored exfoliation is at a specific area or site of the skin of an individual, the skin comprising an exfoliation representing the worst intensity for an individual with exfoliation. In some embodiments, the skin exfoliation is caused by pruritus. In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin exfoliations.

An "effective amount" is an amount sufficient to affect a beneficial or desired result, such as alleviating at least one or more symptoms of AD and/or pruritus. An effective amount as used herein will also include an amount sufficient to delay the development of AD and/or pruritus, alter the course of AD and/or pruritus symptoms (e.g., sleep efficiency), or reverse symptoms of AD and/or pruritus. Therefore, it is not possible to specify an exact "effective amount." However, in any given case, an appropriate "effective amount" can be determined by one of ordinary skill using only routine experimentation.

An effective amount can be administered in one or more administrations, applications or dosage forms. The delivery depends on a number of variables, including the time period over which the individual dosage units are used, the bioavailability of the therapeutic agent, the route of administration, etc. However, it should be understood that for any particular individual, the specific dosage content of the therapeutic agent of the present invention depends on a variety of factors, including the activity of the specific compound employed, the age, weight, general health, sex and diet of the individual, the time of administration, the rate of excretion, the drug combination and the severity of the specific disease being treated and the form of administration. The therapeutic dose can generally be titrated to optimize safety and efficacy. The dose can be determined by a physician and adjusted as necessary to suit the observed therapeutic effect. In general, dose-effect relationships from in vitro and/or in vivo testing can initially provide useful guidance for appropriate dosages for administration to patients. Generally, it will be necessary to administer an amount of compound effective to achieve serum levels commensurate with concentrations found to be effective in vitro. Determination of these parameters is well within the skill. These considerations and effective formulation and administration procedures are well known in the art and are described in standard textbooks.

In some embodiments, the dose of nilizumab or its equivalent administered to a subject is in the range of 0.001 to 1,000 mg/kg body weight of the subject. In some embodiments, the dosage is between about 0.01 and 50 mg/kg, about 0.01 mg/kg to about 0.1 mg/kg, about 0.05 mg/kg to 0.15 mg/kg, about 0.1 mg/kg to about 0.6 mg/kg, about 0.1 mg/kg to about 1 mg/kg, about 0.25 mg/kg to about 0.75 mg/kg, about 0.4 mg/kg to about 0.8 mg/kg, about 0.4 mg/kg to about 1.8 mg/kg, about 0.5 to about 2.5 mg/kg, about 0.8 mg/kg to about 2.2 mg/kg, about 1 mg/kg to about 2.5 mg/kg, about 1 mg/kg to about 3.5 mg/kg, about 1 mg/kg to about 5 mg/kg, about 2 mg/kg to about 4 mg/kg, about 2.5 mg/kg to about 10 mg/kg, about 5 mg/kg to about 10 In some embodiments, the dosage is about 100 mg/kg to about 200 mg/kg, about 100 mg/kg to about 400 mg/kg, about 200 mg/kg to about 500 mg/kg, about 250 mg/kg to about 750 mg/kg, about 500 mg/kg to about 1000 mg/kg of nilizumab or its equivalent per body weight. In preferred embodiments, the dosage is about 0.01 mg/kg to about 0.1 mg/kg, about 0.1 mg/kg to about 0.5 mg/kg, about 0.5 mg/kg to about 1.5 mg/kg, about 1.5 mg/kg to about 2.5 mg/kg, or about 2.5 mg/kg to about 1000 mg/kg of nilizumab or its equivalent per body weight. In some embodiments, the dosage is about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 15 mg/kg, about 25 mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 500 mg/kg or about 1,000 mg/kg. In certain embodiments, the effective amount of nilizumab or its equivalent is about 0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg or about 2.5 mg/kg. In a preferred embodiment, the amount is about 0.5 mg/kg.

In some embodiments, a single dose can be selected, for example, from 1 to 100 mg of the active ingredient (i.e., nilizumab or its equivalent), or more specifically from about 10 to about 90 mg, about 20 to about 80 mg, about 25 to about 70 mg, or about 30 to about 60 mg. For example, in some embodiments, a single dose can be about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 about, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg.

In some embodiments, a single dose may vary over time. For example, a subject may receive an initial "starting dose" that is higher than a "maintenance dose" that is subsequently administered. In some embodiments, a subject may be administered one or more initial starting doses of 60 mg of nivolumab (or its equivalent) followed by subsequent maintenance doses of 30 mg. In other embodiments, the initial dose and subsequent doses may be the same. For example, the initial dose and subsequent dose may be 60 mg. In any of these embodiments, the antibody (nivolumab or its equivalent) may be administered to the subject with or without a second active agent (such as a topical steroid or a topical calcineurin phosphatase inhibitor).

In some embodiments of the methods, nilizumab or its equivalent is administered topically or parenterally. In some embodiments of the methods, nilizumab or its equivalent is administered subcutaneously. In some embodiments, the dose is administered subcutaneously at or near one or more sites of epidermal exfoliation.

In some embodiments, nilizumab or its equivalent is administered daily, every other day, twice a week, three times a week, four times a week, five times a week, six times a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every 10 weeks, once every 11 weeks, once every 12 weeks, twice a year, once a year, and/or as needed based on the onset of symptoms of atopic dermatitis or pruritus. In preferred embodiments, nilizumab or its equivalent is administered once every four weeks or every eight weeks.

In certain embodiments, both the dosage and dosing schedule can be determined prior to initiating a treatment regimen. For example, a subject can be administered about 30 to about 60 mg of nilizumab or its equivalent once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W), alone or in combination with a second active agent (e.g., a topical steroid or a topical calcineurin phosphatase inhibitor). In some embodiments, a subject can be administered an initial starting dose of 60 mg of nilizumab or its equivalent, and thereafter receive a maintenance dose of 30 mg of nilizumab or its equivalent once every four weeks (Q4W). In some embodiments, the maintenance dose may be administered occasionally once every eight weeks (Q8W). Such a treatment regimen may be administered in the presence or absence of concurrent use of topical steroids or topical calcineurin phosphatase inhibitors. In another embodiment, a dose of 60 mg of nilizumab or its equivalent may be administered to an individual once every four weeks (Q4W), wherein the dose is not reduced over time. In some embodiments, the dose may be administered occasionally once every eight weeks (Q8W). Such a treatment regimen may be administered in the presence or absence of concurrent use of topical steroids or topical calcineurin phosphatase inhibitors.

Alternatively, the dosage of a particular regimen can be administered based on the weight of the subject (e.g., mg/kg) rather than a preset dosage. For example, about 0.1 to about 2.0 mg/kg of nilizumab or its equivalent can be administered to a subject once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), once every six weeks (Q6W), once every seven weeks (Q7W), or once every eight weeks (Q8W), alone or in combination with a second active agent (e.g., a topical steroid or a topical calcineurin phosphatase inhibitor). In some embodiments, an individual may be administered an initial starting dose of 0.1, 0.5, or 2.0 mg/kg of nilizumab or its equivalent, and thereafter receive a maintenance dose of nilizumab or its equivalent that is less than the initial starting dose once every four weeks (Q4W). In some embodiments, the maintenance dose may be administered occasionally once every eight weeks (Q8W). Such a treatment regimen may be administered with or without the concurrent use of a topical steroid or a topical calcineurin phosphatase inhibitor. In another embodiment, an individual may be administered a dose of 0.1, 0.5, or 2.0 mg/kg of nilizumab or its equivalent once every four weeks (Q4W), wherein the dose is not reduced over time. In some embodiments, the dose may be administered occasionally, once every eight weeks (Q8W). Such a treatment regimen may be administered with or without concurrent use of topical steroids or topical calcineurin phosphatase inhibitors.

In some embodiments, treatment duration is about one day, about one week, about two weeks, about three weeks, about four weeks, about five weeks, about six weeks, about seven weeks, about eight weeks, about nine weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 24 weeks, about 30 weeks, about 36 weeks, about 40 weeks, about 48 weeks, about 50 weeks, about one year, about two years, about three years, about four years, about five years, or as needed based on the onset of symptoms of atopic dermatitis. In preferred embodiments, treatment duration is about 12 weeks to about 24 weeks, about 12 to about 36 weeks, about 12 to about 48 weeks, or about 24 to about 36 weeks.

According to some embodiments, a use of nilizumab or its equivalent is provided for the manufacture of a medicament for treating atopic dermatitis in an individual suffering from one or more epidermal exfoliations of the skin. In some embodiments, exfoliation is pre-detected and/or scored by a health care professional, by the individual, or by an adult guardian of the individual. In some embodiments, exfoliation is scored according to one or more of the SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and/or TIS methods. In a preferred embodiment, exfoliation is scored according to the SCORAD or PO-SCORAD methods. In some embodiments, exfoliation is scored as moderate to severe. In some embodiments, the exfoliation is scored as 2 to 3. In some embodiments, the individual does not suffer from skin exfoliation scored as none to mild. In some embodiments, the exfoliation is not scored as 0 to 1. In some embodiments, the skin exfoliation is not mild. In some embodiments, the scored exfoliation is at a specific area or part of the skin of the individual, and the skin comprises an average intensity of exfoliation for the individual with exfoliation. In some embodiments, the scored exfoliation is at a specific area or part of the skin of the individual, and the skin comprises an epidermal exfoliation representing the worst intensity of exfoliation for the individual with exfoliation. In some embodiments, the skin exfoliation is caused by pruritus. In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin exfoliations.

According to some embodiments, a method for treating a patient with atopic dermatitis is provided, the method comprising, consisting of, or consisting essentially of: (a) screening a patient with atopic dermatitis for epidermal exfoliation; and (b) treating the patient screened in step (a) by administering an effective amount of nilizumab or its equivalent. In some embodiments, the patient screened in step (a) has epidermal exfoliation. In some embodiments, screening comprises detecting and/or scoring epidermal exfoliation. In some embodiments, epidermal exfoliation is scored according to one or more of SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and/or TIS methods. In a preferred embodiment, epidermal exfoliation is scored according to the SCORAD or PO-SCORAD method. In some embodiments, epidermal exfoliation is scored as moderate to severe. In some embodiments, epidermal exfoliation is scored from 2 to 3. In some embodiments, the patient does not suffer from skin epidermal exfoliation scored as none to mild. In some embodiments, epidermal exfoliation is not scored from 0 to 1. In some embodiments, skin epidermal exfoliation is not mild. In some embodiments, epidermal exfoliation is screened at a specific area or part of the patient's skin, which contains epidermal exfoliation that represents the average intensity of patients with epidermal exfoliation. In some embodiments, epidermal exfoliation is screened at a specific area or site of the patient's skin that contains epidermal exfoliation that represents the worst intensity of an individual with epidermal exfoliation. In some embodiments, the skin exfoliation is caused by pruritus. In some embodiments, the patient has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin exfoliation.

According to some embodiments, a method of improving sleep quality in an individual suffering from atopic dermatitis and one or more skin exfoliations is provided, the method comprising administering to the individual an effective amount of nilizumab or an equivalent thereof. In some embodiments, the improvement in sleep quality is determined by detecting an improvement in one or more of: sleep onset latency, total sleep time, sleep efficiency, or wake time after sleep onset. As described above, sleep efficiency is defined as the total amount of sleep time divided by the total time in bed. In some embodiments, sleep quality is recorded or detected by one or more of an actigraph, motion sensing, video monitoring, and/or self-report. In some embodiments, epidermal exfoliation is pre-detected and/or scored by a health care professional, by an individual, or by an adult guardian of the individual. In some embodiments, epidermal exfoliation is scored according to one or more of the SCORAD, PO-SCORAD, ADAM, EASI, SA-EASI, SASSAD, SSS, and/or TIS methods. In a preferred embodiment, epidermal exfoliation is scored according to the SCORAD or PO-SCORAD methods. In some embodiments, epidermal exfoliation is scored as moderate to severe. In some embodiments, epidermal exfoliation is scored from 2 to 3. In some embodiments, the individual does not suffer from skin epidermal exfoliation scored as none to mild. In some embodiments, epidermal exfoliation is not scored from 0 to 1. In some embodiments, the skin exfoliation is not mild. In some embodiments, the scored exfoliation is at a specific area or site of the skin of an individual, the skin comprising an exfoliation representing an average intensity for an individual with exfoliation. In some embodiments, the scored exfoliation is at a specific area or site of the skin of an individual, the skin comprising an exfoliation representing the worst intensity for an individual with exfoliation. In some embodiments, the skin exfoliation is caused by pruritus. In some embodiments, the subject has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 or more moderate to severe skin exfoliations.

The success of treatment with nilizumab or its equivalent can be determined or assessed by detecting improvement, relief, removal or reduction of one or more symptoms of AD, pruritus or each thereof. For example, success can be determined by detecting improvement in one or more of the following: number of skin exfoliations, intensity of skin exfoliation, exfoliation score, individual's pruritus VAS score, individual's DLQI score, sleep efficiency, sleep onset latency, total sleep time, awakenings after sleep onset, percentage of body surface area affected, individual's E ASI score, the individual's IGA score, degree or amount of dry skin, frequency or presence of itching, severity of itching, redness of the skin, frequency of raised bumps, degree or amount of thickened skin, degree or amount of cracked skin, degree or amount of flaky skin, degree or amount of rough skin, degree or amount of skin sensitivity, and/or degree or amount of swollen skin. In some embodiments, success is not dependent on whether AD and/or pruritus is considered "cured" or "healed" and whether all symptoms subside. EXAMPLES

A randomized, double-blind, placebo-controlled, dose-finding study was conducted to evaluate the long-term efficacy and safety of continuous subcutaneous nivolumab when injected every four weeks (Q4W) or every eight weeks (Q8W) in patients with moderate to severe atopic dermatitis not adequately controlled with topical therapy. The study was published in Kabashima, et al. , J Allergy Clin Immunol (2018) 142(4)1121, which is incorporated by reference in its entirety (including figures). In the primary endpoint analysis, nivolumab administered every four weeks (Q4W) significantly improved pruritus from baseline at week 12, as assessed using the pruritus visual analog scale (VAS). The percentage reporting a reduction in pruritus VAS scores was -44% in the 0.1-mg/kg group, -60% in the 0.5-mg/kg group, and -63% in the 2.0-mg/kg group, compared with -21% in the placebo group (P < .01 for all comparisons). Improvements in AD disease severity and body surface involvement and sleep disturbances were also observed at Week 12, compared with placebo .

Study Design . This study was conducted in 2 parts ( Figure 4 ). For Part A, nilizumab was evaluated for 12 weeks with 4 dosing regimens of 0.1, 0.5, or 2.0 mg/kg subcutaneously Q4W and 2.0 mg/kg subcutaneously Q8W or placebo subcutaneously Q4W. After completion of Part A, patients entered a double-blind extension phase and continued to receive nilizumab at the previously assigned dose for an additional 52 weeks (Weeks 12-64, Part B). Patients previously randomized to placebo in Part A were re-randomized in a 1:1:1 ratio to nivolumab (0.1, 0.5, or 2.0 mg/kg sc Q4W) in Part B using a centralized interactive voice or online response system (placebo-treated patients were not re-randomized to nivolumab 2.0 mg/kg Q8W). All patients were required to enter Part B within 7 days of the final visit in Part A. To maintain blinding in Part B, the study monitoring team, site personnel, and other site/company personnel remained blinded to treatment assignment until the final database lock after study completion. The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Approval was obtained from the local ethics committee or institutional review board for each study center. Written informed consent was provided by all patients.

Study Population . Key inclusion criteria are depicted in Figure 4. Patients were required to complete the Part A treatment period and provide written informed consent to participate in the extension phase to enter Part B.

Study Procedures . In Part B of the study, patients received treatment with 1/3 of the dose of nilizumab (0.1, 0.5, or 2.0 mg/kg) administered subcutaneously Q4W or nilizumab 2.0 mg/kg administered subcutaneously Q8W for 52 weeks. To maintain blinding, patients receiving nilizumab Q8W were given placebo at Week 12 (last visit for Part A), nilizumab at Week 16, and then alternating doses of placebo and nilizumab. Patients were allowed to use emollients, topical treatments (e.g., eye drops), mild topical glucocorticoids (including prednisolone), topical calcineurin inhibitors, and antihistamines (excluding nonselective H1 antihistamines). Patients who had little or no improvement, in the investigator's opinion, in pruritus VAS scores (range, 0 mm [no itch] to 100 mm [worst itching]) and static investigator's global assessment (sIGA) scores (range, 0 [clear] to 5 [very severe disease]) were to use an "effective" topical glucocorticosteroid, such as mometasone furoate 0.1%, as rescue therapy in Part A (at or after Week 4) and an "effective" or "very effective" topical glucocorticosteroid, such as clobetasol propionate 0.05%, in Part B.

Study Assessments . Baseline assessments for patients re-randomized from placebo to nivolumab in Part B were performed at the final visit of Part A or at a separate visit. Patients attended study visits from Week 12 to Week 64 Q4W and safety follow-up visits for 12 weeks (± 5 days) after the last dose of study drug. For consistency, patients were assessed by the same assessor (when possible) at all visits. Assessment training was performed to minimize inter-site and inter-investigator variability. Efficacy assessments were performed as soon as possible after drug cessation at Week 16 to Week 64 Q4W and at the exit visit. Patients completed the pruritus VAS, the pruritus verbal rating scale (VRS; which measures pruritus intensity on a scale of 0 [no itch] to 4 [extreme itch]), and the sleep disturbance VAS (which ranges from 0 [no insomnia] to 100 [complete inability to sleep]) every 7 days during Part B.

Study Endpoints . The primary efficacy endpoint, the percentage improvement from baseline in the pruritus VAS score at Week 12, was assessed during Part A. Secondary efficacy endpoints assessed in Part B (Weeks 12-64) included improvements from baseline in the following: pruritus VAS score, eczema area and severity index (EASI) score (range 0-72, with higher scores indicating worse disease severity), Scoring Atopic Dermatitis (SCORAD; range 0-103, with higher scores indicating more severe disease), body surface area of AD involvement (BSA), and sleep disturbance VAS score. Secondary endpoints also included: the proportion of patients with 25%, 50%, and 75% improvement compared with baseline in pruritus VAS and EASI scores; the proportion of patients with a 2-point or greater improvement compared with baseline in sIGA and pruritus VRS scores; and the proportion of patients receiving rescue therapy. The proportion of patients achieving a pruritus VAS score of less than 30 mm (no or mild itching) was explored in a post hoc analysis. Exploratory efficacy outcomes in Part B included the frequency, duration, and amount of topical corticosteroids used as rescue therapy and Dermatology Life Quality Index scores (DLQI; measured on a scale of 0-30, with higher scores indicating greater impairment). Changes in DLQI scores of 4 points or greater, considered the least clinically important difference, were explored in post hoc analyses. Long-term safety profiles were also assessed.

Statistical Analyses . Secondary and exploratory endpoints in Part B were summarized using descriptive statistics, and no formal statistical comparisons were performed in Part B. No imputation for missing data was performed. Data measured during or after salvage therapy were included in the analysis. The intention-to-treat population was used for efficacy analyses and included all randomized patients who had received at least 1 dose of nivolumab in Part A or B and had at least 1 postdose efficacy assessment. All patients who had received at least 1 dose of nivolumab in Part A or B were included in the safety analysis. Efficacy and safety analyses were performed separately for patients who received nilizumab during the entire 64-week study duration (patients randomized to nilizumab in both Parts A and B) and for patients who crossed over from placebo to nilizumab at Week 12 (patients randomized to placebo in Part A and re-randomized to nilizumab in Part B).

A total of 264 patients were randomized to Part A; of these, 216 completed Part A, and 191 participated in Part B, including 38 re-randomizations from the placebo group ( see Figure 5 ). Of the 191 patients who participated in Part B, 131 (69%) completed Part B. The most common reason for discontinuation from Part B was patient withdrawal from the study (33/191 [17%]), followed by lack of efficacy (10/191 [5%]) and AEs (8/191 [4%]). The intention-to-treat population included 248 patients (211 patients randomized to nivolumab in Part A and 37 patients who received placebo in Part A were re-randomized to nivolumab [one re-randomized patient had no evaluable post-dose efficacy data]). The safety population included 249 patients (211 randomized to nivolumab in Part A and 38 patients who received placebo were re-randomized to nivolumab in Part A). Overall, 84% (222/264) of patients who entered the study in Part A or B completed the safety follow-up 12 weeks after the last dose of study drug.

Patients had intense itching at baseline according to the pruritus visual analog scale (VAS) score, and moderate to severe disease according to the static investigator's global assessment (sIGA), body surface area affected by AD (BSA), and eczema area and severity index (EASI) scores. Mean baseline total serum IgE levels are reported in Table 3. The most common current concomitant allergy was allergic rhinitis (n=91), and the most common history of allergy was asthma (n=34). Demographics, baseline characteristics, and baseline severity of AD in patients who received placebo in Part A (randomized to nilizumab Q4W in Part B) were similar between groups. Table 3. Baseline total serum IgE levels in the intention -to-treat ( ITT ) population .

Among patients randomized to receive nilizumab throughout the 64-week study period, the baseline improvements in pruritus VAS scores observed in Part A were maintained or increased from Week 12 to Week 64 ( see Figure 6 ). The greatest improvements throughout the study were observed in the 0.5-mg/kg nilizumab group ( see Table 4 ). The proportion of patients achieving a pruritus VAS score of less than 30 mm was maintained through Week 64 ( Figures 6B and 4 ). Among patients who had received nivolumab in Part A, the mean ± SD percentage change from baseline in EASI score, Scoring Atopic Dermatitis (SCORAD) score, affected BSA, and sleep disturbance VAS score, and the proportion of patients with a 2-point or greater improvement in sIGA or pruritus verbal rating score (VRS) were also maintained or increased from Week 12 to Week 64 (Fig. 7A-C and Table 4 below). Approximately two-thirds (68%, 68%, and 66%) of patients in the 0.1-mg/kg, 0.5-mg/kg, and 2.0-mg/kg Q4W nivolumab groups, respectively, and almost three-quarters (74%) of patients in the 2.0-mg/kg Q8W group who remained on therapy at Week 64 had a 75% improvement in EASI score (Table 5 below). Table 4. Percent changes from baseline in secondary and exploratory endpoints at Week 12 and Week 64 in the intention-to-treat ( ITT ) population receiving nivolumab in Part A. * Post hoc analyses Table 5. Patients with 25 % , 50 % , and 75 % improvement from baseline in pruritus VAS and EASI scores at Week 12 and Week 64 in the intention-to-treat ( ITT ) population receiving nilizumab in Part A ( data presented as numerical percentages ) . Data were included after rescue therapy.

In patients who received placebo in Part A and switched to nivolumab at Week 12, treatment responses on pruritus VAS scores were found by Week 16 (i.e., 4 weeks after switching to active treatment) and were maintained at Week 64 (1 year after switching to active treatment, see Table 6 below). In general, mean ± SD percentage changes from Week 12 baseline to Week 16 in SCORAD scores, EASI scores, affected BSA, and sleep disturbance VAS scores indicated improvements that were maintained or increased from Week 16 to Week 64 ( see Table 6). However, these data were affected by outliers in a small number of patients included in each group, with higher degrees of change found at each visit (see Table 6). Table 6. Percent Changes from Baseline ( Week 12 ) in Secondary and Exploratory Endpoints at Week 16 ( 4 weeks after the first nivolumab dose in Part B ) and Week 64 for the Intent-to-Treat ( ITT ) Population Who Received Placebo in Part A ( Including Data After Salvage Therapy ) . * Post-mortem analysis

Among patients randomized to receive nivolumab throughout the 64-week study period, the median duration of topical glucocorticoid use decreased with increasing nivolumab dose (0.5 mg/kg or more), ranging from 27.0 weeks (range, 1-62 weeks) in the 0.1-mg/kg Q4W group to 8.0 weeks (range, 1-57 weeks) and 7.5 weeks (range, 1-59 weeks) in the 0.5-mg/kg and 2.0-mg/kg Q4W groups, respectively, and 3.0 weeks (range, 1-48 weeks) in the 2.0-mg/kg Q8W group ( see Table 7). Table 7. Duration of use and cumulative dose of topical glucocorticoids from baseline ( * ) to on-treatment overall and by potency ( * ) throughout the study period in the intention-to-treat population receiving nilizumab in Part A ( data are shown as median ranges ) . † Potency of topical glucocorticoids as defined by the National Institute for Health and Care Excellence (see Atopic eczema in children. Management of atopic eczema in children from birth up to the age of 12 years. Clinical guideline. 2007. *Baseline values not available (zero) because patients were not allowed to use potent or very potent topical glucocorticoids within 2 weeks before randomization or mild or moderately potent topical glucocorticoids within 1 week before randomization. Topical glucocorticoids were not allowed during Part A of the study except as rescue therapy at Week 4 or later.

The median cumulative dose of topical glucocorticoid therapy decreased with increasing nilizumab dose (0.5 mg/kg or more), ranging from 137.4 g (range, 2-2,245 g) in the 0.1-mg/kg Q4W group to 60.7 g (range, 2-822 g), 55.8 g (range, 1-1,174 g), and 44.7 g (range, 10-250 g) in the 0.5-mg/kg and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W groups, respectively ( see Table 7). However, there was a high degree of variability among patients for the duration and dose of topical glucocorticoid therapy, limiting the number of evaluable patients to the total number of patients receiving glucocorticoid therapy (18/30, 17/24, and 20/27 in the 0.1-mg/kg, 0.5-mg/kg, and 2.0-mg/kg Q4W groups, respectively, and 11/24 in the 2.0-mg/kg Q8W group). The proportion of patients receiving "very effective" topical glucocorticoids was similar across groups, whereas the proportion of patients receiving "effective" agents was greatest in the lowest nilizumab Q4W group (63% [19/30] in the 0.1-mg/kg group, 42% [10/24] in the 0.5-mg/kg group, and 56% [15/27] in the 2.0-mg/kg group). Duration and cumulative doses of topical glucocorticoids in evaluable patients tended to decrease with increasing doses for patients receiving "effective,""moderatelyeffective," and "weak" agents ( see Table 7); available data were limited to "very effective" agents.

Dermatology Life Quality Index (DLQI) total scores decreased progressively throughout the 64-week period in patients randomized to nivolumab Q4W and Q8W, with a greater proportion of patients showing a decrease of 4 points or more in total scores at Week 64 compared to Week 12 ( Figure 7 and Table 4). Similar trends were observed in patients receiving placebo in Part A ( see Table 6).

Overall, no new safety concerns were identified following long-term use of nivolumab. Among patients randomized to nivolumab throughout the study duration (64 weeks), similar proportions had at least 1 AE (83% to 89% of patients) or at least 1 treatment-related AE (37% to 48%) during the study ( see Table 8 below). The most common AEs in these patients (≥ 5% of patients randomized to nivolumab throughout the study duration) were nasopharyngitis (27%), worsening of AD (25%), increased blood creatine phosphoconvertase (11%), upper respiratory tract infection (9%), headache (8%), peripheral edema (6%), and abscesses (6%). The most common treatment-related AEs (≥ 2% of patients randomized to nivolumab during the entire study period) were worsening of AD (8%), upper respiratory tract infection (4%), nasopharyngitis (4%), peripheral edema (3%), increased blood creatine phosphotransferase level (3%), and injection site reactions (2%). All treatment-related AEs, except nasopharyngitis and injection site reactions, occurred at a slightly higher rate in the 2.0-mg/kg Q4W group than in the other study groups. The proportion of patients randomized to nivolumab who experienced new-onset AEs decreased over time throughout the 64-week study period, with the majority of AEs reported within the 12 weeks prior to the study ( see Table 9 below). Most AEs were mild or moderate in intensity during the study. SAEs occurred in 9 (17%) patients receiving 2.0 mg/kg nivolumab Q8W compared with 3 to 4 (6% to 8%) patients in the Q4W treatment group ( see Table 8). Six SAEs reported in 5 patients were considered related to study treatment. Five patients (1 in the 0.5-mg/kg Q4W group, 2 in the 2.0-mg/kg Q4W group, and 2 in the 2.0-mg/kg Q8W group) also had 1 SAE of AD worsening, which was considered treatment related in 1 patient. Table 8. Adverse events ( AEs ) during the total 64- week study period in patients randomized to nivolumab throughout the study period . * Patients who received placebo during Part A

The proportion of patients experiencing new-onset SAEs was evenly distributed over the study duration ( see Table 9 below). After adjusting for drug exposure, the rates of AEs and SAEs among patients randomized to nivolumab for the 64-week study period were higher in the 2.0-mg/kg Q8W group compared with the 0.1-mg/kg, 0.5-mg/kg, and 2.0-mg/kg Q4W groups (Table 10); however, no increase in specific AEs was observed. Study treatment was discontinued due to AEs in 7 (13%), 3 (6%), 5 (10%), and 6 (12%) patients randomized to nivolumab during the 64-week study period on nivolumab 0.1-mg/kg, 0.5-mg/kg, and 2.0-mg/kg Q4W and 2.0-mg/kg Q8W, respectively ( see Table 11). Ten patients, all in Part A , discontinued the study prematurely due to worsening of AD. Table 9. New-onset adverse events ( AEs ) and severe adverse events ( SAEs ) by period in patients randomized to nivolumab during the entire study period ( safety population ) . Table 10. Exposure-adjusted adverse events ( AEs ) expressed as number of event-years per 100 patient- years based on the ratio of the number of events observed to the total number of patient - years of exposure . *Patients who received nilizumab during Parts A and B. † Patients who received placebo during Part A. Table 11. Adverse events ( AEs ) leading to treatment withdrawal in patients randomized to nilizumab throughout the study period . *One patient withdrew from the study due to an AE after the last injection of study drug and is not listed.

In patients who were re-randomized from placebo to nivolumab in Part B, AEs were reported in 67% to 92% of patients in the treatment group ( see Table 12). The most common AEs were similar to those seen throughout the study ( see Table 12). One SAE was reported in 1 patient who received placebo during Part A. Two patients who received placebo during Part A discontinued treatment due to AEs after randomization to nivolumab in Part B. Most injection-related reactions (IRRs) occurred during Part A of the study, with no trend toward dose-related effects (12 patients with 13 events in Part A and 4 patients with 5 events in Part B). Almost all IRRs were local reactions, predominantly mild in severity, and mostly considered treatment -related. One IRR led to study treatment discontinuation (exfoliative dermatitis). Table 12. Adverse events ( AEs ) in Part B patients randomized to receive placebo in Part A ( safety population ) . *SAE for Diverticulitis, †Asthma, ‡Bronchoalveolar Hyperresponsiveness

This study evaluated the efficacy and tolerability of nilizumab (anti-IL-31 receptor A mAb) for the treatment of patients with AD not adequately controlled by topical therapies. The study demonstrated that improvements in measures of pruritus, dermatitis, and sleep relative to placebo in the 12-week placebo-controlled portion of the study (Part A) were maintained or increased with long-term treatment up to 64 weeks (Extend Phase: Part B). Consistent with the results of Part A, there was no indication that 2.0-mg/kg nilizumab administered Q4W or Q8W was more effective than the 0.5-mg/kg dose, although the study was not designed to formally compare different dosing groups. In Part B, patients were allowed to use mild topical glucocorticoids, with potent or very potent topical glucocorticoids allowed as rescue therapy. During the study, the duration and cumulative dose of topical glucocorticoid therapy were lower in patients who received higher (≥ 0.5 mg/kg) doses of nivolumab; however, the limited number of patients precludes any conclusions. These findings suggest that the absence of dose-dependent reactions in patients in the 0.1-mg/kg group (which would have resulted in increased efficacy of nivolumab with higher doses) may have been influenced by the greater use of topical glucocorticoid therapy.

AD and the accompanying pruritus impair the quality of life (QoL) of patients with the disease. The reduction in Dermatology Life Quality Index (DLQI) scores observed during Part A of the study was maintained throughout the long-term extension, indicating a prolonged relief of the impact of symptoms on daily life. These findings are consistent with the early improvements in pruritus observed within the first week of nivolumab treatment in Part A of the study.

Overall, nivolumab was well tolerated through 64 weeks. The safety profile was comparable to that seen in Part A, with no new AEs observed in the extension study. The incidence of IRRs was lower in Part B, suggesting that tolerability of nivolumab injections improved over time.

In summary, nilizumab was effective and generally well tolerated when administered for up to 64 weeks in patients with moderate to severe AD that was not adequately controlled by previous topical therapy. Treatment with nilizumab resulted in clinically significant reductions in pruritus and dermatitis. No new safety concerns were identified with long-term nilizumab use.

Figures 1A - 1C provide an atlas of representative images of epidermal exfoliation and its corresponding Scoring Atopic Dermatitis Index (SCORAD) score. The images are from the European Task Force Consensus Report on Atopic Dermatitis, entitled "Severity Scoring of Atopic Dermatitis: The SCORAD Index" (Stalder, JF et al., Dermatology (1993), 186: 23-31). Figure 1A depicts mild epidermal exfoliation with a score of 1. Figure 1B depicts moderate epidermal exfoliation with a score of 2. Figure 1C depicts severe epidermal exfoliation with a score of 3. White arrows indicate exemplary epidermal exfoliation.

Figures 2A - 2D . Representative images of epidermal exfoliation on the wrist of an individual. Epidermal exfoliation was scored according to the SCORAD method, as indicated: Figure 2A depicts no epidermal exfoliation (i.e., no epidermal exfoliation) with a score of 0. Figure 2B depicts mild epidermal exfoliation with a score of 1. Figure 2C depicts moderate epidermal exfoliation with a score of 2. Figure 2D depicts severe epidermal exfoliation with a score of 3.

Figures 3A - 3D provide atlases of representative images of epidermal exfoliation and its corresponding Eczema Area and Severity Index (EASI) scores. Epidermal exfoliation was scored according to the EASI method, as indicated: Figure 3A depicts no epidermal exfoliation (i.e., no epidermal exfoliation) at a score of 0. Figure 3B depicts mild epidermal exfoliation at a score of 1. Figure 3C depicts moderate epidermal exfoliation at a score of 2. Figure 3D depicts severe epidermal exfoliation at a score of 3.

Figure 4. Graphical depiction of study design. *During Part A, patients in the nilizumab 2.0 mg/kg Q8W group received placebo at Week 4; during Part B, patients received placebo at Week 12, nilizumab at Week 16, and then received alternating doses of placebo and nilizumab. **Number of patients randomized to Part B. †Number of patients at Week 64. ‡Safety follow-up was conducted 12 weeks after the last dose of study drug. FU : follow-up; TCI : topical calcineurin inhibitor; TCS : topical glucocorticoid; w : week.

FIG5 is a graphical depiction of the results from Parts A and B of the Phase II study.

Figure 6. Plots of pruritus visual analogue scale (VAS) scores. Figure 6A plots the percentage change in pruritus VAS scores from baseline. Data are presented as mean ± SE. Figure 6B plots the proportion of patients with pruritus VAS scores less than 30 mm (post hoc analysis).

Figure 7. Graphical depictions of the changes from baseline in key secondary and exploratory endpoints in the intention-to-treat (ITT) population receiving nilizumab in Part A (including data after rescue therapy). Figure 7A depicts the percent change in EASI score (mean ± SE). Figure 7B depicts the proportion of patients with an sIGA score of 0 or 1 (percent). Figure 7C depicts the percent change from baseline in the sleep disturbance visual analog scale (VAS) (mean ± SE). Figure 7D depicts the proportion of patients with a 4-point or greater reduction in DLQI (percent; post hoc analysis).

Claims (23)

A use of nemolizumab for the manufacture of a medicament for treating atopic dermatitis in an individual suffering from one or more moderate to severe skin exfoliations, wherein the nemolizumab is present in the medicament in an amount of about 30 mg to about 60 mg, and wherein the treatment continues for a period of at least 64 weeks. For use as claimed in claim 1, wherein the skin epidermal exfoliation is moderate. For use as claimed in claim 1, wherein the skin epidermal exfoliation is severe. For use as claimed in claim 1, wherein the skin exfoliation is assigned a score of at least 2 on the SCORAD scale. The use of any one of claims 1 to 4, wherein the nilizumab is present in the drug in an amount of 30 mg to 60 mg. The use of any one of claims 1 to 4, wherein the drug is administered topically or parenterally. The use of any one of claims 1 to 4, wherein the drug is administered subcutaneously. The use of any one of claims 1 to 4, wherein the drug is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. The use of any one of claims 1 to 4, wherein the drug further comprises a carrier. For use as claimed in claim 9, wherein the carrier is a pharmaceutically acceptable carrier. The use of any one of claims 1 to 4, wherein the nilizumab is present in the drug in an amount of about 30 mg or about 60 mg. The use of any one of claims 1 to 4, wherein the nilizumab is present in the drug in an amount of 30 mg or 60 mg. A use of an effective amount of nemolizumab for the manufacture of a medicament for improving sleep quality in an individual suffering from atopic dermatitis and having one or more moderate to severe skin exfoliations, wherein the nemolizumab is present in the medicament in an amount of about 30 mg to about 60 mg, and wherein the improvement persists for a period of at least 64 weeks. For use as claimed in claim 13, wherein the skin epidermal exfoliation is moderate. For use as claimed in claim 13, wherein the skin epidermal exfoliation is severe. For use as claimed in claim 13, wherein the skin exfoliation is assigned a score of at least 2 on the SCORAD scale. The use of any one of claims 13 to 16, wherein the nilizumab is present in the drug in an amount of 30 mg to 60 mg. The use of any one of claims 13 to 16, wherein the drug is administered topically or parenterally. The use of any one of claim 13 to 16, wherein the drug is administered subcutaneously. The use of any one of claims 13 to 16, wherein the drug is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. The use of any of claims 13 to 16, wherein improvement in sleep quality is determined by detecting improvement in one or more of: sleep onset latency, total sleep time, sleep efficiency, or wake time after sleep onset. The use of any one of claims 13 to 16, wherein the nilizumab is present in the drug in an amount of about 30 mg or about 60 mg. The use of any one of claims 13 to 16, wherein the nilizumab is present in the amount of 30 mg or 60 mg in the drug.